Hyperthermia is currently applied in conjunction with radiation therapy for the treatment of malignant diseases. Some success has been obtained in clinical trials, especially where relatively small and superficial tumors have been treated. Difficulties have been encountered in successfully treating larger and deep seated tumors. These problems have been associated with an inability to reach temperature goals. The inability to reach thermal dose goals has been a result of inadequate hyperthermia equipment and undesired toxicities such as pain. Reaching temperatures greater than 41 degrees C throughout tumor volumes has seldom been achievable even though the goals have commonly been set at 43 degrees C for 1 hour. These clinical trial designs have largely been based upon basic research using rodent cell and animal models. Recent research has demonstrated that human tumor cells are generally more resistant to being killing by 43 degrees C heating than rodent cells, but some human tumor cells are relatively sensitive to long duration heating at 41 degrees C. In addition to possible heat induced killing, human cells have been shown to be sensitized to low dose-rate irradiation (LDR) when heated at 41 degrees C during irradiation. Combining long duration, mild temperature hyperthermia (LDMH) (<42 degrees C for 6 hr or more) with radiation therapy could potentially lead to improvement of tumor response. LDMH is ideally suited for combination with brachytherapy because the temperature goals are achievable and simultaneous heating will optimize radiation sensitization. 1) The primary goal of this project is to determine whether LDMH is superior to short duration 43 degrees C heating in directly killing human tumor cells and sensitizing them to radiation. This will e accomplished by measuring thermal enhancement of radiation induced killing of human tumor cells. Human tumor conditions will be modeled with growth arrested tissue culture systems, multicell spheroids, and xenograph tumors in nude mice. Tumor type specificity of thermal enhancement will be determined by using a variety of cell lines from human tumors commonly treated with brachytherapy. The role of LDMH in sensitizing high dose-rate brachytherapy (HDR) will also be determined in vitro. 2) The second goal is to determine the role of tumor environmental conditions on LDMH sensitization of LDR and direct LDMH induced cell killing. 3) The final goal is to investigate the basic cellular mechanisms of LDMH sensitization of radiation and direct cell killing by determining the effects of LDMH on interference with signal transduction pathways, DNA strand break repair, synthesis of radiation repair proteins, nuclear protein binding, and modification of cell cycle and proliferation. The information obtained in this investigation will determine the conditions which will produce optimal LDMH sensitization of brachytherapy and tumor cell killing.